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1.
Cancer Cell ; 37(3): 403-419.e6, 2020 03 16.
Artigo em Inglês | MEDLINE | ID: mdl-32183952

RESUMO

Natural killer/T cell lymphoma (NKTCL) is an aggressive and heterogeneous entity of non-Hodgkin lymphoma, strongly associated with Epstein-Barr virus (EBV) infection. To identify molecular subtypes of NKTCL based on genomic structural alterations and EBV sequences, we performed multi-omics study on 128 biopsy samples of newly diagnosed NKTCL and defined three prominent subtypes, which differ significantly in cell of origin, EBV gene expression, transcriptional signatures, and responses to asparaginase-based regimens and targeted therapy. Our findings thus identify molecular networks of EBV-associated pathogenesis and suggest potential clinical strategies on NKTCL.


Assuntos
Herpesvirus Humano 4/genética , Linfoma de Células T/genética , Animais , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Dosagem de Genes , Regulação Neoplásica da Expressão Gênica , Genômica , Humanos , Linfoma de Células T/mortalidade , Linfoma de Células T/patologia , Linfoma de Células T/virologia , Terapia de Alvo Molecular , Mutação , Células T Matadoras Naturais/patologia , Filogenia , Transcriptoma , Sequenciamento Completo do Genoma , Ensaios Antitumorais Modelo de Xenoenxerto , Peixe-Zebra
2.
Nat Commun ; 11(1): 438, 2020 01 23.
Artigo em Inglês | MEDLINE | ID: mdl-31974378

RESUMO

Dysfunction of invariant natural killer T (iNKT) cells in tumor microenvironment hinders their anti-tumor efficacy, and the underlying mechanisms remain unclear. Here we report that iNKT cells increase lipid biosynthesis after activation, and that is promoted by PPARγ and PLZF synergically through enhancing transcription of Srebf1. Among those lipids, cholesterol is required for the optimal IFN-γ production from iNKT cells. Lactic acid in tumor microenvironment reduces expression of PPARγ in intratumoral iNKT cells and consequently diminishes their cholesterol synthesis and IFN-γ production. Importantly, PPARγ agonist pioglitazone, a thiazolidinedione drug for type 2 diabetes, successfully restores IFN-γ production in tumor-infiltrating iNKT cells from both human patients and mouse models. Combination of pioglitazone and alpha-galactosylceramide treatments significantly enhances iNKT cell-mediated anti-tumor immune responses and prolongs survival of tumor-bearing mice. Our studies provide a strategy to augment the anti-tumor efficacy of iNKT cell-based immunotherapies via promoting their lipid biosynthesis.


Assuntos
Imunoterapia/métodos , Lipídeos/biossíntese , Células T Matadoras Naturais/fisiologia , Microambiente Tumoral/imunologia , Animais , Carcinoma Hepatocelular/metabolismo , Carcinoma Hepatocelular/patologia , Colesterol/metabolismo , Galactosilceramidas/farmacologia , Regulação da Expressão Gênica , Humanos , Interferon gama/metabolismo , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas/patologia , Melanoma Experimental/imunologia , Melanoma Experimental/patologia , Camundongos Endogâmicos C57BL , Células T Matadoras Naturais/efeitos dos fármacos , Células T Matadoras Naturais/patologia , PPAR gama/genética , PPAR gama/metabolismo , Pioglitazona/farmacologia , Proteína de Ligação a Elemento Regulador de Esterol 1/genética , Proteína de Ligação a Elemento Regulador de Esterol 1/metabolismo , Microambiente Tumoral/efeitos dos fármacos
3.
Lancet Oncol ; 21(2): 306-316, 2020 02.
Artigo em Inglês | MEDLINE | ID: mdl-31879220

RESUMO

BACKGROUND: Extranodal natural killer T-cell lymphoma (NKTCL; nasal type) is an aggressive malignancy with a particularly high prevalence in Asian and Latin American populations. Epstein-Barr virus infection has a role in the pathogenesis of NKTCL, and HLA-DPB1 variants are risk factors for the disease. We aimed to identify additional novel genetic variants affecting risk of NKTCL. METHODS: We did a genome-wide association study of NKTCL in multiple populations from east Asia. We recruited a discovery cohort of 700 cases with NKTCL and 7752 controls without NKTCL of Han Chinese ancestry from 19 centres in southern, central, and northern regions of China, and four independent replication samples including 717 cases and 12 650 controls. Three of these independent samples (451 cases and 5301 controls) were from eight centres in the same regions of southern, central, and northern China, and the fourth (266 cases and 7349 controls) was from 11 centres in Hong Kong, Taiwan, Singapore, and South Korea. All cases had primary NKTCL that was confirmed histopathologically, and matching with controls was based on geographical region and self-reported ancestry. Logistic regression analysis was done independently by geographical regions, followed by fixed-effect meta-analyses, to identify susceptibility loci. Bioinformatic approaches, including expression quantitative trait loci, binding motif and transcriptome analyses, and biological experiments were done to fine-map and explore the functional relevance of genome-wide association loci to the development of NKTCL. FINDINGS: Genetic data were gathered between Jan 1, 2008, and Jan 23, 2019. Meta-analysis of all samples (a total of 1417 cases and 20 402 controls) identified two novel loci significantly associated with NKTCL: IL18RAP on 2q12.1 (rs13015714; p=2·83 × 10-16; odds ratio 1·39 [95% CI 1·28-1·50]) and HLA-DRB1 on 6p21.3 (rs9271588; 9·35 × 10-26 1·53 [1·41-1·65]). Fine-mapping and experimental analyses showed that rs1420106 at the promoter of IL18RAP was highly correlated with rs13015714, and the rs1420106-A risk variant had an upregulatory effect on IL18RAP expression. Cell growth assays in two NKTCL cell lines (YT and SNK-6 cells) showed that knockdown of IL18RAP inhibited cell proliferation by cell cycle arrest in NKTCL cells. Haplotype association analysis showed that haplotype 47F-67I was associated with reduced risk of NKTCL, whereas 47Y-67L was associated with increased risk of NKTCL. These two positions are component parts of the peptide-binding pocket 7 (P7) of the HLA-DR heterodimer, suggesting that these alterations might account for the association at HLA-DRB1, independent of the previously reported HLA-DPB1 variants. INTERPRETATION: Our findings provide new insights into the development of NKTCL by showing the importance of inflammation and immune regulation through the IL18-IL18RAP axis and antigen presentation involving HLA-DRB1, which might help to identify potential therapeutic targets. Taken in combination with additional genetic and other risk factors, our results could potentially be used to stratify people at high risk of NKTCL for targeted prevention. FUNDING: Guangdong Innovative and Entrepreneurial Research Team Program, National Natural Science Foundation of China, National Program for Support of Top-Notch Young Professionals, Chang Jiang Scholars Program, Singapore Ministry of Health's National Medical Research Council, Tanoto Foundation, National Research Foundation Singapore, Chang Gung Memorial Hospital, Recruitment Program for Young Professionals of China, First Affiliated Hospital and Army Medical University, US National Institutes of Health, and US National Cancer Institute.


Assuntos
Biomarcadores Tumorais/genética , Proliferação de Células , Subunidade beta de Receptor de Interleucina-18/genética , Linfoma Extranodal de Células T-NK/genética , Células T Matadoras Naturais/patologia , Ásia , Biomarcadores Tumorais/metabolismo , Estudos de Casos e Controles , Linhagem Celular Tumoral , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Humanos , Interleucina-18/metabolismo , Subunidade beta de Receptor de Interleucina-18/metabolismo , Desequilíbrio de Ligação , Linfoma Extranodal de Células T-NK/imunologia , Linfoma Extranodal de Células T-NK/metabolismo , Linfoma Extranodal de Células T-NK/patologia , Células T Matadoras Naturais/imunologia , Células T Matadoras Naturais/metabolismo , Fenótipo , Prognóstico , Locos de Características Quantitativas , Medição de Risco , Fatores de Risco , Transdução de Sinais , Transcriptoma
4.
Drug Des Devel Ther ; 13: 3579-3589, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31802846

RESUMO

Purpose: Diammonium glycyrrhizinate (DG) is a replacement for glycyrrhizic acid, which is used as a hepatic protector in clinical practice for most liver diseases. The potential role of immune response during autoimmune hepatitis-induced by concanavalin A (Con A)-remains to be elucidated. Methods: C57BL/6J mice were treated with two different doses of DG (75 and 200 mg/kg) 2 hrs before administering Con A. The mice were sacrificed after administering Con A for 0, 6, and 24 hrs. Liver damage grade and serum alanine aminotransferase (ALT), aspartate aminotransferase (AST) and total bilirubin levels were evaluated. The expression level of cleaved-caspase 3 in liver was detected by Western blotting. Inflammatory cytokines such as tumor necrosis factor α (TNF-α), interleukin-6 (IL-6), and interferon γ (IFN-γ) in liver were detected by RT-PCR. Thymus, peripheral blood, spleen, and liver tissues were collected to analyze the percentages of NKT cells, subsets of CD4+CD25-CD69+ and CD8+CD69+ T cells, and subsets of regulatory T cells (Tregs). Results: Our results revealed that DG pre-treatment significantly decreased the serum ALT and AST levels and improved the histological damage in Con A-induced autoimmune liver injury. Pre-treatment with DG down-regulated the inflammatory cytokines upon challenge with Con A. The DG pre-treatment inhibited the apoptosis of T lymphocytes in the thymus. Further, it effectively suppressed the proliferation of CD4+CD25-CD69+ and CD8+CD69+ subsets in the peripheral blood and spleen. In addition, the DG pretreatment significantly downregulated the frequency of NKT cells, while upregulating the frequency of Tregs in the liver. Conclusion: We believe that the potential protective effect of DG against Con A-induced hepatitis may be partially attributed to its inhibitory activities on inflammatory cytokines in the livers, lymphocyte apoptosis in the thymus, NKT cells proliferation, and activation of CD8+T cells; further, there may also be a possibility of DC promoting Tregs proliferation.


Assuntos
Anti-Inflamatórios/farmacologia , Doença Hepática Induzida por Substâncias e Drogas/tratamento farmacológico , Ácido Glicirrízico/farmacologia , Hepatite Autoimune/tratamento farmacológico , Células T Matadoras Naturais/efeitos dos fármacos , Linfócitos T Reguladores/efeitos dos fármacos , Animais , Proliferação de Células/efeitos dos fármacos , Doença Hepática Induzida por Substâncias e Drogas/patologia , Concanavalina A , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Hepatite Autoimune/patologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Estrutura Molecular , Células T Matadoras Naturais/patologia , Relação Estrutura-Atividade , Linfócitos T Reguladores/patologia
5.
Iran J Immunol ; 16(4): 291-298, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31885006

RESUMO

BACKGROUND: NK (natural killer) and NKT (natural killer T) cells, as components of innate immune system, play a crucial role in tumor progression and dissemination. OBJECTIVE: To investigate the percentages of NK cells, NKT cells, iNKT (invariant natural killer T) cells, total T lymphocytes as well as activated T lymphocytes, in tumor draining lymph nodes (TDLNs) of patients with breast cancer (BC) and their association with different clinic-pathological features of the patients. METHODS: Axillary lymph nodes were obtained from 30 Iranian women with breast cancer. After routine pathological evaluations, mononuclear cells were separated from their lymph nodes and incubated with appropriate fluorochrome conjugated monoclonal antibodies specific for CD3, HLA-DR, CD16/56, and Vα24Jα18-TCR. Data were collected on a four-color flow cytometer and analyzed by CellQuest software. RESULTS: The mean percentages of NK (CD3-CD16/56+), NKT (CD3+CD16/56+) and iNKT (Vα24Jα18-TCR+) cells in TDLNs mononuclear cells of BC patients were 2.04%, 2.44% and 0.1%, respectively. A significant decrease in the percentages of NK and iNKT subsets in patients with grade I was observed compared to grade III (p=0.03 and p=0.01, respectively). Moreover, NK cells were increased in patients with grade III of BC compared to grade II (p= 0.003). CONCLUSION: The increase in the percentage of NK and iNKT cells in TDLNs of patients with higher grade of BC might suggest a suppressive phenotype for these cells in breast cancer, which merit more functional investigation.


Assuntos
Antígenos de Diferenciação/imunologia , Neoplasias da Mama/imunologia , Citometria de Fluxo , Células Matadoras Naturais/imunologia , Linfonodos/imunologia , Células T Matadoras Naturais/imunologia , Adulto , Neoplasias da Mama/patologia , Feminino , Humanos , Irã (Geográfico) , Células Matadoras Naturais/patologia , Linfonodos/patologia , Pessoa de Meia-Idade , Células T Matadoras Naturais/patologia
6.
Front Immunol ; 10: 2493, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31695700

RESUMO

Therapy with Tyrosine Kinase Inhibitors (TKI) aiming stable deep molecular response is the gold standard to treat Chronic Myeloid Leukemia (CML). NKT-like cells (CD3+CD56+) combine characteristics of T and NK cells. The physiopathological role of these cells remains unknown although the literature refers their association with inflammation, autoimmune diseases, and cancer. Since the information regarding the role of NKT-like cells in CML is rare, we aimed at the characterization of these cells in CML patients treated with TKIs. Peripheral blood NKT-like cells from 48 CML patients and 40 healthy donors were analyzed by multiparametric flow cytometry. Functional tests consisting of co-culture with leukemic target cells (K562 cell line) were used to measure degranulation and cytokine production. Our results revealed that NKT-like cells are decreased in treated CML patients, although they present increased expression of activation markers (CD69 and HLA-DR), increased degranulation (CD107a) and impaired IFN-γ production. Significantly alterations on the expression of tumor recognition (NCRs and NKp80), and immune regulation receptors (LAG-3, TIM-3, and CD137) by NKT-like cells were observed in CML patients. Second generation TKIs increased cell activation (CD69) and decreased expression of NKp44 and NKp80 by NKT-like cells from CML patients when compared to Imatinib. CML patients that achieved deep molecular response (MR4.5) presented downregulation of NKp44 and LAG-3. Further studies are needed to clarify the role of these cells as biomarkers of therapy response and also to evaluate their value for discrimination of better candidates for sustained treatment-free remission after TKI discontinuation.


Assuntos
Antígenos de Diferenciação/imunologia , Regulação Leucêmica da Expressão Gênica/efeitos dos fármacos , Leucemia Mielogênica Crônica BCR-ABL Positiva/tratamento farmacológico , Leucemia Mielogênica Crônica BCR-ABL Positiva/imunologia , Células T Matadoras Naturais/imunologia , Proteínas de Neoplasias/imunologia , Inibidores de Proteínas Quinases/administração & dosagem , Feminino , Regulação Leucêmica da Expressão Gênica/imunologia , Humanos , Células K562 , Leucemia Mielogênica Crônica BCR-ABL Positiva/patologia , Masculino , Células T Matadoras Naturais/patologia
7.
Front Immunol ; 10: 2355, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31649670

RESUMO

iNKT cells are CD1d-restricted T cells recognizing lipid antigens. The prototypic iNKT cell-agonist α-galactosylceramide (α-GalCer) alongside compounds with similar structures induces robust proliferation and cytokine production of iNKT cells and protects against cancer in vivo. Monoclonal antibodies (mAbs) that detect CD1d-α-GalCer complexes have provided critical information for understanding of antigen presentation of iNKT cell agonists. Although most iNKT cell agonists with antitumor properties are α-linked glycosphingolipids that can be detected by anti-CD1d-α-GalCer mAbs, ß-ManCer, a glycolipid with a ß-linkage, induces strong antitumor immunity via mechanisms distinct from those of α-GalCer. In this study, we unexpectedly discovered that anti-CD1d-α-GalCer mAbs directly recognized ß-ManCer-CD1d complexes and could inhibit ß-ManCer stimulation of iNKT cells. The binding of anti-CD1d-α-GalCer mAb with ß-ManCer-CD1d complexes was also confirmed by plasmon resonance and could not be explained by α-anomer contamination. The binding of anti-CD1d-α-GalCer mAb was also observed with CD1d loaded with another ß-linked glycosylceramide, ß-GalCer (C26:0). Detection with anti-CD1d-α-GalCer mAbs indicates that the interface of the ß-ManCer-CD1d complex exposed to the iNKT cell TCR can assume a structure like that of CD1d-α-GalCer, despite its disparate carbohydrate structure. These results suggest that certain ß-linked monoglycosylceramides can assume a structural display similar to that of CD1d-α-GalCer and that the data based on anti-CD1d-α-GalCer binding should be interpreted with caution.


Assuntos
Anticorpos Monoclonais Murinos/imunologia , Apresentação do Antígeno/imunologia , Antígenos CD1d/imunologia , Galactosilceramidas , Células T Matadoras Naturais/imunologia , Animais , Antígenos CD1d/química , Galactosilceramidas/química , Galactosilceramidas/imunologia , Humanos , Camundongos , Camundongos Endogâmicos BALB C , Células T Matadoras Naturais/patologia , Relação Estrutura-Atividade
8.
J Allergy Clin Immunol ; 144(6): 1478-1489, 2019 12.
Artigo em Inglês | MEDLINE | ID: mdl-31606262

RESUMO

This current review explores selected and as yet insufficiently investigated frontiers in current alopecia areata (AA) pathobiology research, with an emphasis on potential "new" players in AA pathobiology that deserve more systematic exploration and therapeutic targeting. Indeed, new evidence suggests that CD8+ T cells, which have long been thought to be the central players in AA pathobiology, are not the only drivers of disease. Instead, subsets of natural killer (NK) and so-called "unconventional" T cells (invariant NK T cells, γδ T cells, classic NK cells, and type 1 innate lymphoid cells), all of which can produce large amounts of IFN-γ, might also drive AA pathobiology independent of classical, autoantigen-dependent CD8+ T-cell functions. Another important new frontier is the role of regulatory lymphocyte subsets, such as regulatory T cells, γδ regulatory T cells, NKT10 cells, and perifollicular mast cells, in maintaining physiologic hair follicle immune privilege (IP); the extent to which these functions are defective in patients with AA; and how this IP-protective role could be restored therapeutically in patients with established AA. Broadening our AA research horizon along the lines suggested above promises not only to open the door to innovative and even more effective immunotherapy strategies for AA but will also likely be relevant for other autoimmune disorders in which pathobiology, ectopic MHC class I expression, and IP collapse play an important role.


Assuntos
Alopecia em Áreas/imunologia , Doenças Autoimunes/imunologia , Imunidade Inata , Alopecia em Áreas/patologia , Autoantígenos/imunologia , Doenças Autoimunes/patologia , Pesquisa Biomédica , Linfócitos T CD8-Positivos/imunologia , Linfócitos T CD8-Positivos/patologia , Humanos , Células Matadoras Naturais/imunologia , Células Matadoras Naturais/patologia , Células T Matadoras Naturais/imunologia , Células T Matadoras Naturais/patologia
9.
Front Immunol ; 10: 2187, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31620124

RESUMO

Natural killer T (NKT) cells are CD1d restricted T cells that mostly recognize lipid antigens. These cells share characteristics with both adaptive and innate immune cells and have multiple immunoregulatory roles. In a manner similar to innate immune cells, they respond quickly to stimuli and secrete large amounts of cytokines, amplifying and modulating the immune response. As T cells, they express T cell receptors (TCRs) and respond in an antigen-specific manner like conventional T cells. There are at least two subtypes of NKT cells, type I and type II, that differ in the nature of their TCR, either semi-invariant (type I) or diverse (type II). The two sub-types generally have opposing functions in tumor immunity, with type I promoting and type II suppressing tumor immunity, and they cross-regulate each other, forming an immunoregulatory axis. The tumor has multiple mechanisms by which it can evade immune-surveillance. One such mechanism involves alteration in tumor lipid repertoire and accumulation of lipids and fatty acids that favor tumor growth and evade anti-tumor immunity. Since NKT cells mostly recognize lipid antigens, an altered tumor lipid metabolic profile will also alter the repertoire of lipid antigens that can potentially affect their immune-modulatory function. In this review, we will explore the effects of alterations in the lipid metabolites on tumor growth, antigen cross-presentation, and overall effect on anti-tumor immunity, especially in the context of NKT cells.


Assuntos
Antígenos de Neoplasias/imunologia , Metabolismo dos Lipídeos/imunologia , Lipídeos/imunologia , Células T Matadoras Naturais/imunologia , Neoplasias/imunologia , Evasão Tumoral , Animais , Humanos , Células T Matadoras Naturais/patologia , Neoplasias/patologia
10.
Front Immunol ; 10: 1849, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31440243

RESUMO

Non-NK group 1 innate lymphoid cells (ILC1s), mainly investigated in the mucosal areas of the intestine, are well-known to contribute to anti-parasitic and anti-bacterial immune responses. Recently, our group revealed that lung ILC1s become activated during murine influenza infection, thereby contributing to viral clearance. In this context, worldwide seasonal influenza infections often result in severe disease outbreaks leading to high morbidity and mortality. Therefore, new immune interventions are urgently needed. In contrast to NK cells, the potential of non-NK ILC1s to become functionally tailored by immune modulators to contribute to the combat against mucosal-transmitted viral pathogens has not yet been addressed. The present study aimed at assessing the potential of ILC1s to become modulated by iNKT cells activated through the CD1d agonist αGalCerMPEG. Our results demonstrate an improved functional responsiveness of murine lung and splenic ILC1s following iNKT cell stimulation by the mucosal route, as demonstrated by enhanced surface expression of TNF-related apoptosis-inducing ligand (TRAIL), CD49a and CD28, and increased secretion of IFNγ. Interestingly, iNKT cell stimulation also induced the expression of the immune checkpoint molecules GITR and CTLA-4, which represent crucial points of action for immune regulation. An in vivo influenza infection model revealed that intranasal activation of ILC1s by αGalCerMPEG contributed to increased viral clearance as shown by reduced viral loads in the lungs. The findings that ILC1s can become modulated by mucosally activated iNKT cells in a beneficial manner emphasize their up to now underestimated potential and renders them to be considered as targets for novel immune interventions.


Assuntos
Imunidade nas Mucosas , Vírus da Influenza A/imunologia , Células T Matadoras Naturais/imunologia , Infecções por Orthomyxoviridae/imunologia , Animais , Antígenos de Diferenciação/imunologia , Feminino , Camundongos , Camundongos Knockout , Células T Matadoras Naturais/patologia , Infecções por Orthomyxoviridae/patologia
11.
J Immunol ; 203(7): 1808-1819, 2019 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-31462506

RESUMO

Invariant NKT (iNKT) cells are innate-like T lymphocytes that recognize and respond to glycolipid Ags such as α-galactosylceramide (α-GalCer). This unique property has been exploited in clinical trials for multiple malignancies. While investigating mouse iNKT cell responses to α-GalCer in vivo, we found a dramatically enlarged tissue-resident population surprisingly coexpressing select dendritic cell, NK cell, and B cell markers. Further phenotypic and functional analyses revealed the identity of this B220+CD11c+MHC class II+NK1.1+ population as precursors to mature NK (pre-mNK) cells, which also expressed high levels of proliferation and tissue retention markers but diminished sphingosine-1-phosphate receptor 1, a receptor that facilitates tissue trafficking. Accordingly, FTY720, a sphingosine-1-phosphate receptor 1 antagonist, failed to prevent pre-mNK cells' intrahepatic accumulation. We found iNKT cell-driven expansion of pre-mNK cells to be dependent on IL-12 and IL-18. Although α-GalCer-transactivated pre-mNK cells lost their capacity to process a model tumor Ag, they selectively expressed granzyme A and directly lysed YAC-1 thymoma cells through granule exocytosis. They also contributed to ß2 microglobulin-deficient target cell destruction in vivo. Therefore, α-GalCer treatment skewed pre-mNK cell responses away from an APC-like phenotype and toward killer cell-like functions. Finally, the ability of α-GalCer to reduce the pulmonary metastatic burden of B16-F10 mouse melanoma was partially reversed by in vivo depletion of pre-mNK cells. To our knowledge, our findings shed new light on iNKT cells' mechanism of action and glycolipid-based immunotherapies. Therefore, we introduce pre-mNK cells as a novel downstream effector cell type whose anticancer properties may have been overlooked in previous investigations.


Assuntos
Antígenos de Neoplasias/imunologia , Galactosilceramidas/imunologia , Células Matadoras Naturais/imunologia , Melanoma Experimental/imunologia , Células T Matadoras Naturais/imunologia , Timoma/imunologia , Animais , Antígenos de Neoplasias/genética , Linhagem Celular Tumoral , Cloridrato de Fingolimode/farmacologia , Galactosilceramidas/genética , Imunoterapia , Interleucina-12/genética , Interleucina-12/imunologia , Interleucina-18/genética , Interleucina-18/imunologia , Células Matadoras Naturais/patologia , Melanoma Experimental/genética , Melanoma Experimental/patologia , Melanoma Experimental/terapia , Camundongos , Camundongos Knockout , Células T Matadoras Naturais/patologia , Metástase Neoplásica , Receptores de Esfingosina-1-Fosfato/antagonistas & inibidores , Receptores de Esfingosina-1-Fosfato/genética , Receptores de Esfingosina-1-Fosfato/imunologia , Timoma/genética , Timoma/patologia , Timoma/terapia
12.
Acta Derm Venereol ; 99(12): 1136-1142, 2019 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-31449312

RESUMO

Psoriasis is considered to be a cytokine-driven immune-mediated disease, although the cell cytotoxicity mechanisms involved remain unrecognized. Herein, we analyzed granulysin expression in different lymphocyte subsets of peripheral blood of 40 psoriatic patients (20 with severe and 20 with mild psoriasis) and seven sample of psoriatic skin. The simultaneous detection of intracellular granulysin and cell surface antigens was performed using flow cytometry in peripheral blood and immunohistochemistry in skin lesions. The frequency of granulysin+ cells, mean fluorescence intensity for granulysin, and the frequency of CD8+ T lymphocytes, NK cells, and NKT cells expressing granulysin molecules in peripheral blood were significantly higher in patients with severe psoriasis compared to mild disease and healthy individuals. These were also correlated with disease severity. Furthermore, granulysin+ cells, CD8+granulysin+ T lymphocytes, and CD56+granulysin+ NK cells were present in a higher frequency in the epidermal basal cell layer and in the dermal infiltrate of lesional skin as compared to non-lesional and healthy skin. In conclusion, granulysin+ cytotoxic cells are upregulated in blood and lesions of patients with psoriasis suggesting the involvement of granulysin mediated cytotoxicity in psoriasis pathogenesis.


Assuntos
Antígenos de Diferenciação de Linfócitos T/metabolismo , Linfócitos T CD8-Positivos/metabolismo , Células Matadoras Naturais/metabolismo , Células T Matadoras Naturais/metabolismo , Psoríase/metabolismo , Pele/metabolismo , Adolescente , Adulto , Idoso , Antígenos de Diferenciação de Linfócitos T/sangue , Linfócitos T CD8-Positivos/imunologia , Linfócitos T CD8-Positivos/patologia , Estudos de Casos e Controles , Estudos Transversais , Feminino , Humanos , Células Matadoras Naturais/imunologia , Células Matadoras Naturais/patologia , Masculino , Pessoa de Meia-Idade , Células T Matadoras Naturais/imunologia , Células T Matadoras Naturais/patologia , Psoríase/sangue , Psoríase/diagnóstico , Psoríase/imunologia , Índice de Gravidade de Doença , Pele/imunologia , Pele/patologia , Regulação para Cima , Adulto Jovem
13.
Immunogenetics ; 71(7): 489-499, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-31297569

RESUMO

Epigenetic modifications have been shown to be important for immune cell differentiation by regulating gene transcription. However, the role and mechanism of histone methylation in the development and differentiation of iNKT cells in rheumatoid arthritis (RA) mice have yet to be deciphered. The DBA/1 mouse RA model was established by using a modified GPI mixed peptide. We demonstrated that total peripheral blood, thymus, and spleen iNKT cells in RA mice decreased significantly, while iNKT1 in the thymus and spleen was increased significantly. PLZF protein and PLZF mRNA levels were significantly decreased in thymus DP T cells, while T-bet protein and mRNA were significantly increased in thymus iNKT cells. We found a marked accumulation in H3K27me3 around the promoter regions of the signature gene Zbtb16 in RA mice thymus DP T cells, and an accumulation of H3K4me3 around the promoters of the Tbx21 gene in iNKT cells. The expression levels of UTX in the thymus of RA mice were significantly reduced. The changes in the above indicators were particularly significant in the progressive phase of inflammation (11 days after modeling) and the peak phase of inflammation (14 days after modeling) in RA mice. Developmental and differentiation defects of iNKT cells in RA mice were associated with abnormal methylation levels (H3K27me3 and H3K4me3) in the promoters of key genes Zbtb16 (encoding PLZF) and Tbx21 (encoding T-bet). Decreased UTX of thymus histone demethylase levels resulted in the accumulation of H3K27me3 modification.


Assuntos
Artrite Reumatoide/patologia , Lisina/metabolismo , Células T Matadoras Naturais/patologia , Regiões Promotoras Genéticas , Timo/fisiologia , Animais , Artrite Experimental/patologia , Diferenciação Celular , Epigênese Genética , Regulação da Expressão Gênica , Histona Desmetilases/genética , Histona Desmetilases/metabolismo , Metilação , Camundongos Endogâmicos DBA , Proteína com Dedos de Zinco da Leucemia Promielocítica/genética , Proteína com Dedos de Zinco da Leucemia Promielocítica/metabolismo , Baço/patologia , Proteínas com Domínio T/genética , Proteínas com Domínio T/metabolismo
14.
J Clin Exp Hematop ; 59(2): 56-63, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31257346

RESUMO

Other iatrogenic immunodeficiency-associated lymphoproliferative disorders (OIIA-LPDs) with a T- or NK-cell phenotype are markedly rare, with only a limited number of cases having been reported thus far. Methotrexate (MTX) is the most common agent used for OIIA-LPD patients, and 43 cases of MTX-associated T-LPDs (MTX T-LPDs) and five cases of MTX-associated NK/T-LPDs (MTX NK-LPDs) have been described. In addition to MTX T-LPDs and MTX NK/T-LPDs, T-LPD and NK/T-LPDs have been reported in patients receiving other immunosuppressive agents such as thiopurines, TNF antagonists, and cyclosporine. Hepatosplenic T-cell lymphoma (HSTL) is specifically associated with iatrogenic immunodeficiency, and 10% of HSTL cases develop in patients receiving thiopurines and/or TNF antagonists for inflammatory bowel disease (IBD). In this review, we focused on MTX T-LPD, MTX NK/T-LPD, and HSTL in patients with IBD. These T- and NK/T-cell associated OIIA-LPDs are the most common in daily medical practice.


Assuntos
Síndromes de Imunodeficiência/patologia , Transtornos Linfoproliferativos/patologia , Linfócitos T/patologia , Animais , Humanos , Doença Iatrogênica/epidemiologia , Síndromes de Imunodeficiência/induzido quimicamente , Imunossupressores/efeitos adversos , Imunossupressores/uso terapêutico , Doenças Inflamatórias Intestinais/tratamento farmacológico , Transtornos Linfoproliferativos/induzido quimicamente , Metotrexato/efeitos adversos , Metotrexato/uso terapêutico , Células T Matadoras Naturais/efeitos dos fármacos , Células T Matadoras Naturais/patologia , Linfócitos T/efeitos dos fármacos
16.
Clin Immunol ; 205: 125-129, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-31152891

RESUMO

Nasal polyps (NP) are associated with inflamed mucosa of unknown etiology. The role of T cells in nasal polyposis is unclear. Invariant natural killer T cells (iNKT) can promote Th2 responses and have been implicated in some types of asthma. As there are shared inflammatory pathways involved in asthma and NPs, we evaluated the frequency of iNKT in 17 patients with NPs, but without asthma. A median of 6% polyp cells were T lymphocytes, of which iNKT were 0 to 2.38% (mean 0.674%). In the matched group (n = 10), iNKT in NPs was significantly higher than PBMCs (1.057% vs 0.155%, P < 0.05). Relative expression of Vα24 to TCR-beta genes in polyps (n = 14) was higher than blood in matched samples (n = 4). The presence of greater proportions of iNKT in NPs than in blood suggests that iNKT may play a role in the pathogenesis of nasal polyposis.


Assuntos
Pólipos Nasais/patologia , Células T Matadoras Naturais/patologia , Adolescente , Adulto , Doença Crônica , Feminino , Genes Codificadores da Cadeia beta de Receptores de Linfócitos T/genética , Humanos , Imunoglobulina E/metabolismo , Contagem de Leucócitos , Leucócitos Mononucleares , Masculino , Pessoa de Meia-Idade , Pólipos Nasais/genética , Pólipos Nasais/metabolismo , Pólipos Nasais/cirurgia , Receptores de Antígenos de Linfócitos T/genética , Rinite/genética , Rinite/metabolismo , Rinite/patologia , Sinusite/genética , Sinusite/metabolismo , Sinusite/patologia , Adulto Jovem
17.
PLoS One ; 14(5): e0216815, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31071196

RESUMO

Using induced pluripotent stem cells (iPSCs) to derive chimeric antigen receptor-modified T (CAR-T) cells has great industrial potential. A previous study used αß T cell-derived CAR-modified iPSCs to produce CAR-T cells. However, these αß T cells are restricted to autologous use and only recognize single cancer antigen. To make CAR-T alternative for allogeneic use, we reprogrammed γδ T cell into iPSCs (γδ T-iPSCs) to circumvent the risk of graft-versus-host disease. To target multiple cancer-associated antigens, we used an "NK cell-promoting" protocol to differentiate γδ T-iPSCs and to induce expression of natural killer receptors (NKRs). Through such two-step strategy, mimetic γδ T cells endowed with an array of NKRs and thus designated as "γδ natural killer T (γδ NKT) cells" were derived. With no/low-level expression of inhibitory killer cell immunoglobulin-like receptors (KIRs) and immune checkpoint receptors, γδ NKT cells may provide a potent "off-the-shelf" cytotoxic cell source to recognize multiple ubiquitous antigens in a broad spectrum of cancers.


Assuntos
Antígenos de Neoplasias/imunologia , Células-Tronco Pluripotentes Induzidas/imunologia , Células T Matadoras Naturais/imunologia , Neoplasias/imunologia , Receptores de Antígenos de Linfócitos T gama-delta/imunologia , Receptores de Antígenos Quiméricos/imunologia , Antígenos de Neoplasias/genética , Células HCT116 , Células Hep G2 , Humanos , Células-Tronco Pluripotentes Induzidas/patologia , Células K562 , Células MCF-7 , Células T Matadoras Naturais/patologia , Neoplasias/genética , Receptores de Antígenos de Linfócitos T alfa-beta/genética , Receptores de Antígenos de Linfócitos T alfa-beta/imunologia , Receptores de Antígenos Quiméricos/genética , Células THP-1
18.
Front Immunol ; 10: 1011, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31134081

RESUMO

Human monocytic ehrlichiosis (HME) is a potentially life-threatening tick-borne rickettsial disease (TBRD) caused by the obligate intracellular Gram-negative bacteria, Ehrlichia. Fatal HME presents with acute ailments of sepsis and toxic shock-like symptoms that can evolve to multi-organ failure and death. Early clinical and laboratory diagnosis of HME are problematic due to non-specific flu-like symptoms and limitations in the current diagnostic testing. Several studies in murine models showed that cell-mediated immunity acts as a "double-edged sword" in fatal ehrlichiosis. Protective components are mainly formed by CD4 Th1 and NKT cells, in contrast to deleterious effects originated from neutrophils and TNF-α-producing CD8 T cells. Recent research has highlighted the central role of the inflammasome and autophagy as part of innate immune responses also leading to protective or pathogenic scenarios. Recognition of pathogen-associated molecular patterns (PAMPS) or damage-associated molecular patterns (DAMPS) triggers the assembly of the inflammasome complex that leads to multiple outcomes. Recognition of PAMPs or DAMPs by such complexes can result in activation of caspase-1 and -11, secretion of the pro-inflammatory cytokines IL-1ß and IL-18 culminating into dysregulated inflammation, and inflammatory cell death known as pyroptosis. The precise functions of inflammasomes and autophagy remain unexplored in infections with obligate intracellular rickettsial pathogens, such as Ehrlichia. In this review, we discuss the intracellular innate immune surveillance in ehrlichiosis involving the regulation of inflammasome and autophagy, and how this response influences the innate and adaptive immune responses against Ehrlichia. Understanding such mechanisms would pave the way in research for novel diagnostic, preventative and therapeutic approaches against Ehrlichia and other rickettsial diseases.


Assuntos
Autofagia/imunologia , Ehrlichia/imunologia , Ehrlichiose/imunologia , Inflamassomos/imunologia , Animais , Linfócitos T CD8-Positivos/imunologia , Linfócitos T CD8-Positivos/patologia , Ehrlichiose/patologia , Humanos , Células T Matadoras Naturais/imunologia , Células T Matadoras Naturais/patologia , Células Th1/imunologia , Células Th1/patologia
19.
J Allergy Clin Immunol ; 144(2): 549-560.e10, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-30851295

RESUMO

BACKGROUND: Natural killer T (NKT) cells express a T-cell receptor that recognizes endogenous and environmental glycolipid antigens. Several subsets of NKT cells have been identified, including IFN-γ-producing NKT1 cells, IL-4-producing NKT2 cells, and IL-17-producing NKT17 cells. However, little is known about the factors that regulate their differentiation and respective functions within the immune system. OBJECTIVE: We sought to determine whether the polycomb repressive complex 2 protein enhancer of zeste homolog 2 (Ezh2) restrains pathogenicity of NKT cells in the context of asthma-like lung disease. METHODS: Numbers of invariant natural killer T (iNKT) 1, iNKT2, and iNKT17 cells and tissue distribution, cytokine production, lymphoid tissue localization, and transcriptional profiles of iNKT cells from wild-type and Ezh2 knockout (KO) iNKT mice were determined. The contribution of NKT cells to development of spontaneous and house dust mite-induced airways pathology, including airways hyperreactivity (AHR) to methacholine, was also assessed in wild-type, Ezh2 KO, and Ezh2 KO mice lacking NKT cells. RESULTS: Ezh2 restrains development of pathogenic NKT cells, which induce spontaneous asthma-like disease in mice. Deletion of Ezh2 increased production of IL-4 and IL-13 and induced spontaneous AHR, lung inflammation, mucus production, and IgE. Increased IL-4 and IL-13 levels, AHR, lung inflammation, and IgE levels were all dependent on iNKT cells. In house dust mite-exposed animals Ezh2 KO resulted in enhanced AHR that was also dependent on iNKT cells. CONCLUSION: Ezh2 is a central regulator of iNKT pathogenicity and suppresses the ability of iNKT cells to induce asthma-like pathology.


Assuntos
Asma/imunologia , Proteína Potenciadora do Homólogo 2 de Zeste/imunologia , Pulmão/imunologia , Células T Matadoras Naturais/imunologia , Animais , Asma/genética , Asma/patologia , Fatores de Transcrição Hélice-Alça-Hélice Básicos/genética , Fatores de Transcrição Hélice-Alça-Hélice Básicos/imunologia , Proteína Potenciadora do Homólogo 2 de Zeste/genética , Imunoglobulina E/genética , Imunoglobulina E/imunologia , Inflamação/genética , Inflamação/imunologia , Inflamação/patologia , Interleucina-13/genética , Interleucina-13/imunologia , Interleucina-4/genética , Interleucina-4/imunologia , Pulmão/patologia , Camundongos , Camundongos Knockout , Células T Matadoras Naturais/patologia , Receptores de Hidrocarboneto Arílico/genética , Receptores de Hidrocarboneto Arílico/imunologia
20.
J Biol Chem ; 294(14): 5438-5455, 2019 04 05.
Artigo em Inglês | MEDLINE | ID: mdl-30745361

RESUMO

Asthma is a common inflammatory pulmonary disorder involving a diverse array of immune cells such as proinflammatory T helper 2 (Th2) cells. We recently reported that intraperitoneal injection of α-galactosylceramide (α-GalCer) can stimulate the lung invariant natural killer T (iNKT) cells and does not lead to airway inflammation in WT mice. Other studies indicate that iNKT cells play an important role in inducing regulatory T cells (Treg cells) and peripheral tolerance. Using iNKT cell- knockout mice, functional inactivation of Treg cells, and co-culture experiments in murine asthma models, we investigated the immunoregulatory effects of α-GalCer treatment before allergen sensitization on Th2 cell responses. We also studied whether α-GalCer's effects require lung Treg cells induced by activated iNKT cells. Our results disclosed that intraperitoneal administration of α-GalCer before allergen sensitization could promote the expansion and suppressive activity of lung CD4+FoxP3+ Treg cells. These effects were accompanied by down-regulated Th2 cell responses and decreased immunogenic maturation of lung dendritic cells in WT mice. However, these changes were absent in CD1d-/- mice immunized and challenged with ovalbumin or house dust mites, indicating that the effects of α-GalCer on Treg cells mainly require iNKT cells. Moreover, functional inactivation of Treg cells could reverse the inhibitory ability of this α-GalCer therapy on Th2 cell responses in a murine asthma model. Our findings indicate that intraperitoneal administration of α-GalCer before the development of asthma symptoms induces the generation of lung Treg cells via iNKT cells and may provide a potential therapeutic strategy to prevent allergic asthma.


Assuntos
Alérgenos/toxicidade , Asma/prevenção & controle , Galactosilceramidas/farmacologia , Células T Matadoras Naturais/imunologia , Linfócitos T Reguladores/imunologia , Células Th2/imunologia , Alérgenos/imunologia , Animais , Asma/induzido quimicamente , Asma/imunologia , Asma/patologia , Células Dendríticas/imunologia , Células Dendríticas/patologia , Modelos Animais de Doenças , Feminino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Knockout , Células T Matadoras Naturais/patologia , Pyroglyphidae/imunologia , Linfócitos T Reguladores/patologia , Células Th2/patologia
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